Responses to a variety of drugs and endogenous substances are altered with "normal" aging. These changes have important implications for physiologic regulation and for pharmacotherapy in the elderly. This application requests continuing support of research activities directed at understanding the sources of variability in physiologic and pharmacologic responses, especially to vasoactive drugs and endogenous compounds. One factor being evaluated as a source of variability in response is aging itself but other protocols are directed at investigating sources of variation for drug classes which are especially important to the elderly. Thus the emphasis will be on drugs commonly used in the elderly (nitrates, alpha and beta antagonists and agonists, antihistamines), on conditions commonly affecting the elderly (hypercholesterolemia), and on the changes in response that can occur during chronic therapy, such as the development of tolerance and dependence. Specific human studies will address the following questions: 1.) Is the observation that there is desensitization to the alpha1-antagonist terazosin indicative of desensitization to other drugs in this class? 2.) Is there a loss in vascular effects of older or newer H1-antagonists during chronic administration of these drugs? 3.) What role do cytochrome P450 enzymes and the glutathione S-transferase enzymes in vascular smooth muscle and endothelium have in determining responses to nitrates and in mediating tolerance to nitrates? 4.) What endogenous factors are important in mediating vascular tone in humans? Does hypercholesterolemia alter tone? How is the influence of various factors regulating vascular tone altered during aging? The technique used to quantitate vascular responses involves infusing one or more compounds into medium-sized veins on the dorsal aspect of the hand and measuring vein diameter. This approach avoids systemic reflexes and allows complete dose-response curves to be generated. Interpatient variability in therapeutic responses is the most important cause of therapeutic failure and drug toxicity in the clinical environment. The long-term goal is to identify and, if possible, quantitate the contribution of various factors influencing drug response in order to develop clinical methods for individualizing drug selection and drug doses in the elderly patient.